Progesterone During Pregnancy: Endocrine–Immune Cross Talk ...animal.ifas.ufl.edu/hansen/publications_pdf/docs/2007_arck.pdf · Progesterone During Pregnancy: Endocrine–Immune

Progesterone During Pregnancy: Endocrine–Immune Cross Talkin Mammalian Species and the Role of StressPetra Arck1, Peter J Hansen2, Biserka Mulac Jericevic3, Marie-Pierre Piccinni4, Julia Szekeres-Bartho5

1Charité, University Medicine Berlin, Berlin, Germany;2Department of Animal Sciences, University of Florida, Gainesville, FL, USA;3Department of Physiology and Immunology, Medical School, University of Rijeka, Rijeka, Croatia;4Center of Excellence for Research, Transfer and High Education DENOTHE of the University of Florence, Department of Internal Medicine –

Immunoallergology unit – viale Morgagni, Florence, Italy;5Department of Medical Microbiology and Immunology Medical School, Pecs University, Pecs, Hungary

Introduction

Pregnancy is characterized by overall hormonal

changes. Progesterone (P) is critical for not only the

establishment but also for the maintenance of preg-

nancy, as its functions support ovulation and uterine

as well as mammary gland development. Compared

to the low levels (1–2 nmol ⁄ L) during the follicu-lar phase of the menstrual cycle P concentrations

increase to 15–20, 35–50, and 20–40 nmol ⁄ L in theearly- mid-, and late-luteal phases respectively.

The major source of P during pregnancy is the cor-

pus luteum of the ovary and, if pregnancy occurs, in

many species, including humans and rodents,

P production is eventually sustained by the pla-

centa.1 In humans, P production gradually rises dur-

ing gestation to reach a level of 3 lg ⁄ g of placentaltissue (1–10 lm), whereas the serum concentrationsof P range from about 100 to 500 nm during preg-

nancy.2 The need for P in maintaining pregnancy is

shown by the fact that blocking of P binding sites

causes abortion in human and also in various animal

species. Besides its endocrine effects P acts as an ‘im-

munosteroid’. Successful pregnancy depends on

maternal tolerance of the fetal ‘semi-allograft’ (Clark

et al., current issue). Here, P blocks very early T-cell

Keywords

NK cells, pregnancy, progesterone

Correspondence

Julia Szekeres Bartho, MD, PhD, Department

of Medical Microbiology and Immunology,

Medical School, Pecs University, 12 Szigeti

Str., H-7643 Pecs, Hungary.

E-mail: [email protected]

Submitted June 16, 2007;

accepted June 21, 2007.

Citation

Arck P, Hansen PJ, Mulac Jericevic B, Piccinni

M-P, Szekeres-Bartho J. Progesterone during

pregnancy: endocrine-immune cross talk in

mammalian species and the role of stress. Am

J Reprod Immunol 2007; 58:268–279

doi:10.1111/j.1600-0897.2007.00512.x

Progesterone is critical for the establishment and the maintenance of

pregnancy, both by its endocrine and immunological effects. The geno-

mic actions of progesterone are mediated by the intracellular progester-

one receptors; A and B. A protein called P-induced blocking factor

(PIBF), by inducing a TH2 dominant cytokine production, mediates the

immunological effects of progesterone. Progesterone plays a role in uter-

ine homing of NK cells and up-regulates HLA-G gene expression, the

ligand for various NK inhibitory receptors. At high concentrations pro-

gesterone is a potent inducer of Th2-type cytokines as well as of LIF and

M-CSF production by T cells. Though a key role for progesterone in cre-

ating local immunosuppression has been conserved during the evolution

of an epitheliochorial placenta, there has been some divergence in the

pattern of endocrine-immunological cross talk in Bovidae. In sheep, uter-

ine serpin, a progesterone-induced endometrial protein, mediates the

immunosuppressive effects of progesterone. Epidemiological studies sug-

gest the role of stress in premature pregnancy termination and exposure

to stress induces abortion in mice via a significant reduction in progester-

one levels, accompanied by reduced serum levels of PIBF. These effects

are corrected by progesterone supplementation. These findings indicate

the significance of a progesterone-dependent immuno-modulation in

maternal tolerance of the fetus, which is discussed in this review.

REVIEW ARTICLE

American Journal of Reproductive Immunology 58 (2007) 268–279 ª 2007 The Authors

268 Journal compilation ª 2007 Blackwell Munksgaard

lymphopoiesis during pregnancy3 and controls the

bias towards a pregnancy protective immune

milieu,4 which involves an immunomodulatory

protein, known as P-induced blocking factor (PIBF).5

Such observations might be just the ‘tip of the ice-

berg’ of insights into the cross talk between the

endocrine and the immune systems,6–8 the underly-

ing mechanisms that operate throughout gestation

are not completely understood.

Progesterone, its receptors and mechanisms of

actions

Progesterone (P), one of the key players in the inter-

action between the endocrine and immune systems,

regulates menstrual bleeding, tissue repair and

regeneration, inflammation, angiogenesis, blastocyst

implantation, and maintenance of pregnancy. These

events result from precisely coordinated activity of

molecular pathways that ensure endometrial cell

proliferation, differentiation, cell survival, leukocyte

trafficking, apoptosis, and angiogenesis.

Genomic and non-genomic pathways mediate the

biological activities of P. The P regulated genomic

pathway depends on two progesterone receptor

(nPR) isoforms, PR-A and PR-B, both members of

the nuclear receptor superfamily of transcription fac-

tors.9,10 PR-A and PR-B are the products of the same

gene, transcribed under control of two distinct pro-

moters. The PR-A and PR-B isoforms differ, in that

PR-B contains an additional N-terminal stretch of

approximately 165 amino acids.

In addition to regulation by P, the transcriptional

activity of nPR isoforms can be regulated through

alternation of expression level, interaction with co-

activators and post-translational modification of

nPR.9,10 Spatial and temporal expression of the PR-A

and PR-B vary in reproductive tissues as a conse-

quence of the developmental and the hormonal sta-

tus as well as of carcinogenesis.

In mice, null mutation of the nPR gene revealed

that transcriptional activity of nPR controls the uter-

ine immune environment as well as endometrial

receptivity and decidualization.11,12 Also functionally

active nPRs in the thymus are required for thymic

involution during pregnancy and for a normal fertil-

ity.13 Studies with mice in which PR-A and PR-B

expression were selectively ablated demonstrate that

PR-A and PR-B isoforms are functionally distinct

transcription factors.13,14 Briefly, P-induced activa-

tion of PR-A is both necessary and sufficient for the

establishment and the maintenance of pregnancy,

but elicits reduced pregnancy-stimulated mammary

gland morphogenesis. In contrast, P-induced

transcriptional activity of the PR-B isoform is insuffi-

cient for implantation and the maintenance of preg-

nancy, and mice lacking PR-A are infertile. These

findings imply that the relative expression of the

two isoforms is critical for the appropriate reproduc-

tive tissue responses to P.15

Although the genomic pathway of P action has

been extensively studied, so far only a few P-regu-

lated genes have been identified in the peri-implan-

tation uterus. These genes include amphiregulin (a

member of EGF superfamily), histidine decarboxyl-

ase (an enzyme that converts histidine to histamine),

Hox-A10 and Hox-A11 (both members of homeobox

gene family), calcitonin (a peptide hormone), proen-

cephalin (neuropeptide), immune response gene 1

(Irg-1), MUC1 (a glycoprotein component of apical

glycocalyx), indian hedgehog (mophogen), and

galectin-1.16

Hox-A10 deficiency in mice leads to severe local

immunological disturbances, characterized by a poly-

clonal proliferation of T cells that occurs in absence

of the normal P-mediated immunosuppression in the

peri-implantation uterus.17 Natural killer (NK) cell

constitute the predominant leukocyte population

present in endometrium at the time of implantation

and early pregnancy (Santoni et al.18, current issue).

Hox-A10 deficiency in mice alters region specific

gene expression and compromises NK cell differenti-

ation, but not trafficking of NK precursors cells dur-

ing decidualization.19

Estrogen-induced MUC1 is expressed by human

villous syncytio- and cytotrophoblast as well as by

invasive extravillous cytotrophoblast.20 It was pro-

posed that blastocyst implantation is regulated by

a uterine barrier, whereby a high density of MUC1

at the epithelial cell surface can inhibit blastocyst

adhesion.21 In mice MUC1 expression in the uterine

epithelium is down-regulated during the window of

implantation, and studies on genetically modified

mice suggest that PR-A antagonizes Muc1 expression,

which may subsequently allow blastocyst adhesion.22

Indian hedgehog (Ihh) is another gene, regulated

by P. Ihh plays a critical role in communication

(required for embryo implantation) between the

uterine epithelium and stroma.23 Ihh belongs to

hedgehog family of morphogens that regulate cell

proliferation, differentiation and cell–cell communi-

cation, all of which may be involved in successful

PROGESTERONE DURING PREGNANCY


Journal compilation ª 2007 Blackwell Munksgaard 269

decidualization and maintenance of fetal tolerance.

Finally, galectin-1, which is also under the

regulation of P, appears to be of importance, since its

expression is down regulated on placental villous tis-

sues from patients with spontaneous miscarriages.24

Non-genomic actions of P include (a) P-induced

acrosomal reaction, (b) P-induced resumption of

meiosis, and (c) P induced decrease in neuronal

excitability and anesthesia.25 The non-genomic

actions are characterized by a fast response to

P (latency of minutes rather than hours) and no

requirement for de novo protein or RNA synthesis.

Non-genomic actions of P appear to operate through

membrane specific G protein-coupled receptors.

Proper functional communication between the

genomic and non-genomic P-regulated signaling

pathways could be critical for the establishment of

a correct endocrine-immune interaction in human

endometrium during the establishment and mainte-

nance of pregnancy.25

Clearly, a profound knowledge of the key molecu-

lar signals that are essential for the establishment of

the receptive uterus will open therapeutic

approaches in the development of new strategies for

the treatment of implantation failures. Although

technological advancement in functional genomics

and proteomics allows identification of the differen-

tially regulated genes during the implantation win-

dow26,27 ethical considerations preclude an in-depth

investigation of early molecular events in humans.

Therefore, animal models, such as mouse knockout

models will continue to be invaluable tools for

studying the molecular events involved in the estab-

lishment and maintenance of pregnancy.28

The effect of P on the immune system

With the exception of human leukocyte (HLA)-C,

polymorphic major histocompatibility complex

(MHC) is not expressed on human trophoblast, and

this creates a unique immunological situation.

Though decidual macrophages and dendritic cells

can present fetal antigens to both decidual CD4+ and

CD8+ cells, trophoblast-presented antigens are unli-

kely to be recognized in an MHC-restricted fashion.

In the decidua, there is a significantly increased

number of activated c ⁄ d TCR-positive cells.29,30 Asmost c ⁄d T cells are capable to recognize unprocessedforeign antigens without MHC restriction, they could

be candidates for ‘seeing’ trophoblast presented anti-

gens. In peripheral blood of healthy pregnant

women the number of c ⁄ d T cells is a significantlyincreased, and almost all of them express nPRs,31

suggesting a prior activation. These cells could be of

decidual origin, which, after activation by tropho-

blast presented antigens, appear in peripheral circu-

lation.

Uterine dendritic cells (DC) have been proposed to

serve as a switchboard between fetal rejection and

tolerance.32–34 DCs are the most potent antigen pre-

senting cells (APCs) involved in the innate immune

response and in the maintenance of tolerance.35 The

regulation of their maturation, migration, and

expression of stimulatory and costimulatory mole-

cules has major consequences on the immune

response, whereby endogenous factors regulating DC

function are poorly understood. Immature DCs exhi-

bit a tolerogenic phenotype, characterized by low

expression of costimulatory molecules (CD40, CD80,

and CD86), low production of proinflammatory

cytokines, increased production of IL-10, and capac-

ity to induce regulatory T cells with suppressive

actions, all of which will promote pregnancy mainte-

nance. Immature DC reside in early pregnancy

decidua in humans32,36 and mice34,37 and possibly

serve as sentinel cells of the tissue environment for

potential danger signals. However, in murine preg-

nancies with high abortion rates, an increase of

mature APC can be observed.34 By blocking crucial

ligands required on APCs to induce T-cell activation,

mechanisms of fetal tolerance are restored in aborton-

prone pregnancies.38 P has been shown to inhibit

mature dendritic cells as well as DC-stimulated pro-

liferation of T cells in a receptor-mediated fashion.39

The effect of P on the immune system of pregnant

women could be partly receptor-mediated.40–43

Recent finding suggest that P might act directly

through membrane specific P receptors to suppress

T-cell activation during pregnancy.44 Following

recognition of fetal antigens, activated maternal c ⁄ dT cells express nPRs,31 and upon P binding, they pro-

duce a mediator namely PIBF.5,45 In urine samples of

healthy pregnant women, PIBF concentration contin-

uously increases until the 37th week of gestation,

followed by a slow decrease until term. In pregnancies

that end up in miscarriage or pre-term delivery, uri-

nary PIBF levels fail to increase during pregnancy.46

By signaling via the Jak ⁄ STAT pathway,47 PIBFinduces a TH2 dominant cytokine production

48 and

in a cytokine-mediated way blocks NK activity.49

Neutralization of endogenous PIBF activity in

pregnant mice by specific anti-PIBF antibody causes

ARCK ET AL.



a significant reduction in the number of viable

fetuses, and this is associated with an increased sple-

nic NK activity, together reduced IL-10 and

increased interferon-c (IFN-c) production of thespleen cells.50 These are corrected by treatment of

the pregnant animals with anti-NK antibodies,50

suggesting that in mice PIBF contributes to the

success of pregnancy and that the major part of its

pregnancy-protective effect lies in controlling NK

activity.

In rodents and also in human hormonally

controlled uterine NK cells play an important role in

creating a suitable environment for the establish-

ment of pregnancy.51 The temporal and spatial distri-

bution of these cells suggests that one of the

functions of these cells might be the control of

placentation. Decidual NK cells secrete an array of

angiogenic factors and induce vascular growth in the

decidua. By producing interleukin-8 and interferon-

inducible protein-10 chemokines decidual NK cells

regulate trophoblast invasion.52

Henderson et al.53 demonstrated the absence of PR

in purified decidual NK cells, and thus a genomic

action of P on these cells is unlikely. Nevertheless,

P affects decidual NK cells in several ways.

Van den Heuvel et al.42 reported that P plays

a role in uterine homing of NK cells by promoting

NK cell interactions with the endothelium. NK cell

migration to the endometrium is also supported by

sex-hormone-induced specific endometrial produc-

tion of chemokines.54

Decidual NK cells show a low spontaneous cyto-

toxic activity in spite of their high perforin con-

tent.55 Many of them express inhibitory receptors

that recognize non-polymorphic MHC molecules.

P has been shown to up-regulate HLA-G gene

expression,56 and the increased availability of P pro-

tects the trophoblast from NK-mediated killing.

Based on their cytokine secretion profile human

CD4+ T helper cells, can be subdivided into at least

three distinct functional subsets.57,58

Human type 1 (Th1) CD4+ T cells that produce

interleukin (IL-2), tumor necrosis factor (TNF-a), andIFN-c are the main effectors of host defense againstinfections by intracellular parasites. On the other

hand, human type 2 (Th2) CD4+ T cells produce IL-4,

IL-5, IL-13 and IL-10, which together with IL-4 inhi-

bit several macrophage functions. A third type (Th0)

produces both Th1- and Th2-type cytokines. Recently

additional CD4+ cell subsets have been identified:

Th3 cells, which produce TGF-b and IL-10,59 Th17

cells, which produce IL-17A and IL-22,60 and

regulatory T cells (T reg) secreting IL-10 and TGF-b.61

Cytokines produced by APCs and lymphocytes

affect the development of Th1 and Th2 responses

both in vitro and in vivo. IFN-c, IL-12, and IFN-aexert critical effects on CD4+ subset maturation by

inducing Th1 expansion,62,63 while IL-4 is needed

for Th2 cell maturation.62 Steroid hormones control

the cytokine profile of T cells. Glucocorticoids and

1,25-dihydroxy-vitamin D3 increase IL-4,64,65

whereas dihydrotestosterone decreases IL-4 and IL-5

production.66 The polypeptide hormone relaxin pre-

dominantly produced by the corpus luteum and

decidua during pregnancy favors the development of

IFN-c-producing T cells.67 In two murine T-cell lines(NIMP-TH1 and EL4) dexamethasone negatively reg-

ulates IL-5 gene expression, whereas testosterone

and P induce the expression of IL-5 gene.68

Progesterone also affects the differentiation of rest-

ing peripheral blood T cells into Th1-, Th0-, or

Th2-like clones and the production of IL-4 by

human T-cell clones4 via the development of anti-

gen-specific CD4+ T cell lines with an enhanced abil-

ity to produce IL-4 and IL-5.4 In addition, P induces

IL-4 mRNA expression and the production of detect-

able amounts of IL-4 in Th1-type T-cell clones (able

to produce IFN-c only without P).4 IL-4 productionby Th1 T-cell clones in response to P was associated

with the expression of CD30 (a molecule preferen-

tially expressed by IL4-producing T cells).4

These results indicate that P at concentrations that

are higher than those found in serum during preg-

nancy, but comparable to those present at the

feto-maternal interface,1 functions as a potent indu-

cer of Th2-type cytokine production, which could be

independently confirmed by others.2 Further, P pro-

motes the development of LIF (leukemia inhibitory

factor),69 as well as macrophage colony-stimulating

factor (M-CSF)-producing T cells.70 Progesterone-

induced LIF (essential for the embryo implantation)

and M-CSF (important for pregnancy development)

production was mediated by IL-4, produced by

T cells in response to P. The effects of P were hor-

mone-specific, as P receptors are found on activated

T cells and P analogues (4 pregnen 20 b-ol 3- one, 4pregnen 20- a ol 3- one, and 5 pregnen 3 b- ol 20-one) have no effect on cytokine production by either

T-cell lines and clones.4,40 The mechanisms by which

P acts on T-cell differentiation are still unknown.

It has been suggested that a Th1 to Th2 switch

at the feto-maternal interface plays a role in the




maintenance of successful pregnancy.71 In line with

this, placental IL-4 mRNA expression in mice was

found to be 5- to 10-fold higher than in peripheral

blood.72 Furthermore, defective IL-4 production by

decidual CD4+ as well as CD8+ T cells, and defective

of IL-10, LIF, and M-CSF production by decidual

CD4+ T cells were detectable in women with unex-

plained recurrent abortion at the time of miscar-

riage.69 These data suggest that in human the

success of pregnancy is associated with the produc-

tion of Th2-type cytokines, LIF and M-CSF by T cells

at materno-fetal interface. P, which, at concentra-

tions comparable with those present at the materno-

fetal interface during pregnancy, is not only a potent

inducer of Th2-type cytokines (i.e. IL-4 and IL-5),4

but also of LIF and M-CSF production by T cells69,70

may be at least in part responsible for a Th2 switch

at maternofetal interface.73 IL-4 produced by decid-

ual Th2 cells can in turn promote the development

of T cells producing LIF and M-CSF,69,70 which seem

to be important for embryo implantation and devel-

opment. Both IL-4 and IL-10 can inhibit the devel-

opment and function of Th1 cells and macrophages,

thus preventing the allograft rejection.

These findings indicate that the immunological

effects of P contribute to the complex network of

regulatory pathways in the cause of fetal allograft

survival.

The effect of stress on the immune response and

the outcome of pregnancy

The hypothalamic-pituitary-adrenal (HPA) axis exerts

an inhibitory effect on the female reproductive system

when activated by stress. Corticotrophin releasing

hormone (CRH) inhibits hypothalamic gonadotropin

releasing hormone (GnRH) secretion, and glucocorti-

coids inhibit pituitary luteinizing hormone and

ovarian steroid hormones, estrogen and P.

Psychosocial stress has been shown to alter cyto-

kine production by peripheral lymphocytes of preg-

nant women during the first trimester of pregnancy.

Some of the pregnancy complications cannot be

explained by either maternal or fetal pathologies.74–77

Several epidemiological studies support the notion

that the onset of miscarriages may be attributable to

high levels of perceived stress. Repeated miscarriages

can induce anxiety and even depression. Emotional

stress, due to repeated pregnancy losses might also

contribute to further miscarriages. However, to date,

the unconfined acceptance of stress as a cause for

pregnancy loss in everyday clinical practice is limited

by contradictory observations.78,79 Such contradic-

tory results may be explained by the diverse experi-

mental design, such as correlating the temporal

coincidence of stressful life events or self-reported

stress perception to the onset of spontaneous

abortion. Further, the lack of appropriate tools to

evaluate stress perception is clearly a limitation in

cohort studies. For humans, little physiological

evidence exists in support of this hypothesis and

thus, identification of risk factors for stress-triggered

miscarriages requires further research.80–82

Emerging evidence indicates that mediators of the

HPA axis, such as CRH and the glucocorticoid corti-

sol may serve as such stress indicators.83 High levels

of glucocorticoids exert adverse effects on the uterus

and fetus, and inhibit pituitary luteinizing hormone,

and ovarian estrogen, and P secretion.84 Such inhibi-

tory effects of stress hormones on the female

reproductive system are responsible for the ‘hypo-

thalamic’ amenorrhea of stress, and – as shown in

mice – may also account for inadequate levels of

P during pregnancy, subsequently resulting in spon-

taneous abortion.84 The concept of stress-triggered

inhibition of P is supported by experimental evi-

dence from animal studies. Exposure to stress in the

form of restraint85 or sound86 induces abortion in

pregnant mice via a significant reduction in P levels,

accompanied by reduced serum levels of P-induced

blocking factor (PIBF) and diminished expression of

PRs at the feto-maternal interface.87 Administration

of the P derivative dydrogesterone increases levels of

PIBF and restores the pregnancy-protective immune

milieu in the mouse model of stress-triggered abor-

tions, as well as in humans with threatened abor-

tion.87–89 Such endocrine-immune cross talk is

exceedingly dependent on a specific CD8+ T-cell

population, since depletion of CD8 led to a termina-

tion of the pregnancy protective effect of P substitu-

tion in mice, whereby the precise phenotype of this

specific, pregnancy-protective CD8 cell population,

e.g. the co-expression of the ab or cd T-cell receptor,remains to be elucidated.88 The notion of decreased

levels of P in response to stress could also be con-

firmed in other mammalian species, such as in

elks.90

In addition to the ‘classical’ stress mediators, such

as CRH, adrenocorticotropin (ACTH), cortisol or

catecholamines,91 the neurotrophin nerve growth

factor (NGF) or the neuropeptide Substance P are

progressively recognized as a pivotal regulator of the

ARCK ET AL.



stress response cascade.92–94 Thus, future research

addressing the potential threat of such stress media-

tors on progesterone production and pregnancy

maintenance is needed.

Endocrine-immune cross talk in Bovidae: insights

into the immunological consequences of evolution

of the epitheliochorial placenta.

Besides mice and humans the Bovidae have been

one of the most extensively studied clades in mam-

malian reproduction; whereby examination of the

specializations acquired by these animals during evo-

lution provides insights into immunological adjust-

ments to pregnancy. Such features are essential in

reproduction in eutherian mammals and represent

clade-specific solutions to the immunological prob-

lem of viviparity.

The Bovidae diverged as a separate family of peco-

ran ruminants about 24–29 million years ago during

the Late Oligocene epoch.95 While the basic pattern

of reproduction in ruminants is similar to other

mammals, there are distinct features including pla-

cental anatomy. Ruminants possess an epitheliocho-

rial placenta characterized by apposition of fetal and

maternal tissues. Invasion of the maternal system

either does not occur or is limited to migration of

trophoblast cells into the maternal endometrial epi-

thelium to form a syncytium (Fig. 1).96,97

Evolutionary advantages conferred by an

epitheliochorial placenta include more efficient

transport of nutrients.96 In addition, fetal-maternal

competition may be reduced in species with epithe-

liochorial species because the mother has greater

control over maternal blood flow to the placenta.96

It is also possible that there are immunological

consequences of epithelichorial placentation. As

compared to species with invasive placenta, access of

maternal leukocytes to fetal placental tissue is

restricted physically by several cell layers and there

may be reduced opportunity for pieces of trophoblast

tissue to enter draining lymph nodes and peripheral

circulation of the mother.

Whether these differences actually confer

increased immunological fitness for the placenta

with respect to maternal immunological recognition

is not known. In any case, the immunological rela-

tionship between the conceptus and mother in Bovi-

dae is similar in many ways to that for other

mammals. Expression of MHC antigens on the tro-

phoblast is largely down-regulated98,99 although, at

least in the cow, there is limited expression of class I

MHC molecules by trophoblast in later pregnancy.99

Down-regulation of MHC antigen expression may be

an important requirement for successful pregnancies:

cloned bovine conceptuses, which experience high

rates of fetal loss, can express aberrantly high

levels of MHC class I protein associated with

Fetal capillary

Endothelium

Maternal capillary

Endothelium

Fetal side Maternal side

Connective

tissueCon

nect

ive

tissu

e

Fetal chorionic epithelium Maternal endometrial epithelium

Epitheliochorial placenta

Endotheliochorial placenta (Endo P) (Endo P)

Hemochorial placenta

Fig. 1 Comparative understanding of the

placenta in different species: Placentas are

variously classified, i.e. by their macroscopic

appearance, or according to its intimacy of

fetal-maternal contact. Here, the main placen-

tal types have been described as epitheliocho-

rial (three maternal layers and three fetal

layers), endotheliochorial (one maternal layer,

three fetal layers), hemochorial (no maternal

layers; three fetal layers). (Note: placentas can

also express a mosaic type). Hence, six cellu-

lar layers that can potentially be between the

fetal and maternal blood cells. Epitheliochorial

(6-layer) placentas are common in pigs, cows,

horses, and sheep. Endotheliochorial (4-layer)

placentas are frequently found in dogs, cats,

seals, and ferrets. Hemochorial placentas

(where the maternal blood cells are in direct

contact with the fetal chorion) are seen in

humans, rats, and mice.114




increased accumulation of maternal lymphocytes in

endometrial stroma.100

Experiments from the sheep indicate that exten-

sive remodeling of the leukocyte population in the

uterus takes place during pregnancy. Macrophages

accumulate in large numbers in the endometrial

stroma during pregnancy101 and granulated cd-Tcells become abundant in luminal epithelium of the

interplacentomal regions during mid- and late-preg-

nancy.102,103 Non-granulated T cells in the glandular

epithelium decline during pregnancy while numbers

of these cells in luminal epithelium first decline and

then return to levels seen in non-pregnant ewes.103

It is not known whether there are changes in NK-

cell populations in the endometrium during preg-

nancy because of the paucity of immunological and

functional assays for these cells in ruminants. Lim-

ited evidence in sheep suggests that there is no large

increase in endometrial NK-cell numbers in late

pregnancy when compared with cyclic ewes.104 It

may be that these cells, which play a crucial role in

vascular remodeling in mice,105 are not important

players in at least some species with epitheliochorial

placentation because of differences in endometrial

vascular architecture.

Use of a unilaterally pregnant model in sheep

(where pregnancy is surgically confined to one uter-

ine horn) has revealed that accumulation of macro-

phages is due to both systemic signals (numbers of

cells in the non-pregnant uterine horn of the unilat-

erally pregnant ewe higher than amounts in uteri of

non-pregnant ewes) and locally produced signals

(number of cells in the uterus of unilaterally ligated

ewes higher in the pregnant horn than in the non-

pregnant horn).102 Accumulation of cd T cells isa result of unidentified systemic signals.103 However,

local placentally derived signals may be involved in

activation of cd T cells. There was increased expres-sion of CD25 from cd T cells isolated from the preg-nant uterine horn of unilaterally pregnant ewes

when compared with the non-pregnant horn.29

As previously outlined, one of the key regulators

of uterine immune function is P. In cattle, the pla-

cental contribution to P synthesis is low throughout

most of pregnancy and also low in sheep until day

50 of pregnancy (gestation length = 147 days). Thus,

for all or part of pregnancy, lymphocytes at the

fetal-maternal interface are probably not exposed to

the high concentrations required to inhibit lympho-

cyte function.106 Administration of P to sheep can

block tissue graft rejection in utero when injected to

achieve concentrations in blood too low to directly

inhibit lymphocyte proliferation.107,108 Thus, P regu-

lates tissue rejection responses indirectly by inducing

secretory molecules from the uterine endometrium

that can regulate immune function.

Interestingly, the major P-induced immunoregula-

tory molecule in sheep is a member of the serine

proteinase inhibitor family called uterine serpin.

Ovine uterine serpin can block lymphocyte prolifera-

tion in vitro in sheep109 and NK-cell-mediated abor-

tion in vivo in mice.110 Cattle, goats, and pigs also

secrete uterine serpin from the endometrium but its

role in immune function in these species has not

been documented. Strikingly, the gene for uterine

serpin is not present in human or mouse as deter-

mined by queries of genomic databases. The gene for

uterine serpin arose early in mammalian evolu-

tion111 and it may be that the gene has been retained

only in species with epitheliochorial placentation.

Local signals controlling macrophage accumulation

and activation status of cd T cells have not beenidentified. The bovine placenta expresses non-classi-

cal MHC antigens,112 and it may be that, as has been

postulated for species with invasive placenta,113

these molecules act to regulate macrophages and

dendritic cells in the uterus to direct immune

responses to favor conceptus survival.

Conclusions

Progesterone is critical for the establishment and the

maintenance of pregnancy, both by its endocrine

and immunological effects, as shown by a progester-

one-dependent immunomodulation in maternal tol-

erance of the fetus, e.g. via PIBF and uterine

homing of NK cells and up-regulation of HLA-G

gene expression in mice and ⁄ or humans. Adequatelevels of progesterone may be inhibited upon high

stress perception, followed by reduced serum levels

of PIBF and diminished expression of progesterone

receptors at the feto-maternal interface. These effects

are corrected by progesterone supplementation.

Some divergence in the pattern of endocrine-

immunological cross talk is present in Bovidae, such

as the lack of placental progesterone synthesis or the

presence of uterine serpin, a progesterone-induced

endometrial protein, which may mediate the immu-

nosuppressive effects of progesterone in sheep. By

reason of their evolutionary conservation, these

may be essential features of vivaparity in eutherian

mammals.

ARCK ET AL.



Acknowledgements

P Arck, B Mulac Jericevic, M-P Piccinni and J Sze-

keres-Bartho are members of the European Network

of Excellence on Embryo Implantation Control, sup-

ported by EU Contract No. 512040.

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